Cancer is the second-leading cause of death in the United States and is a serious public health concern. The current generation of cytotoxic chemotherapeutic agents used for the treatment of cancer is not curative for a majority of patients. For many cancer patients, the use of chemotherapy extends patient-life by only a few months and often results in serious side effects that reduce the quality of life.
Anticancer drugs that are utilized for cancer chemotherapy include cytotoxic nucleoside analogs (Pratt et al., “Antimetabolites” in The Anticancer Drugs, 2nd ed. Oxford University Press, New York. pp. 69-107 (1994)), such as analogs of the four nucleotides that are the principal components of DNA. Examples of cytotoxic analogs include the fluoropyrimidines (FPs) such as 5FU, which are analogs of dU, the precursor for dT, the arabinosyl nucleotides AraC and AraA, which are analogs of dC and dA, respectively, dFdC (gemcitabine), which is an analog of dC, and 6-mercaptopurine, which is an analog of dI, the precursor of dG.
The current paradigm in chemical drug development involves restrictions on the molecular weight and the charge of candidate drugs. The rationale for these restrictions is that drugs must have high bioavailability and must enter cells either by passive diffusion or by well-characterized molecular transport processes. Thus, while the activated forms of nucleoside analogs are typically 5′-O-mono-, di-, or tri-phosphates, cytotoxic nucleoside analogs are either administered as the nucleobase, if the active form of the drug is the 2′-deoxyribonucleotide (e.g. 5FU as a precursor for FdUMP), or as the nucleoside, if the activated form of the drug has a non-native sugar (e.g. AraC as a precursor for AraCTP). However, 2′-deoxyribonucleosides are generally ineffective as drugs because of the facile cleavage of the glycosidic bond.
The requirement for intracellular metabolic activation of these drugs decreases their effectiveness for at least two reasons: 1) cancer cells can become resistant to the drug by down-regulating the expression of cellular enzymes that are required for metabolic activation; and 2) competing metabolic processes may divert the drug to undesirable products in the cell. For example, 5FU is administered as a precursor to FdUMP but is also metabolized to FUTP and incorporated into RNA, resulting in toxicity towards cells of the gasterointestinal tract (Pritchard et al., Proc. Natl. Acad. Sci. USA 94: 1795-1799 (1997)).
The principal cause for the ineffectiveness of cytotoxic chemotherapeutic drugs in current use (e.g., 5-fluorouracil (5FU)) is a failure of the activated form of the drug to accumulate in cancer cells at sufficient concentrations to cause cancer cell death (Longley et al., Nature Cancer 3: 330-338 (2003)). Malignant cells that survive drug treatment become drug-resistant, and refractory to further chemotherapy.
For example, despite great efforts utilizing conventional chemotherapy strategies, metastatic prostate cancer (PC) currently remains incurable and an inevitably fatal disease. This is largely due to the fact that chemotherapeutic drugs are not effective at killing tumors in late-stage PC because PC cells do not accumulate drugs at sufficient concentrations to cause cell death. The ability to deliver activated cytotoxic drugs specifically to PC cells in vivo is likely to result in a reduction of the mortality rate (currently 30,000 per year) for patients with advanced PC (American Cancer Society Facts and Figures 2004.
Targeted delivery of cytotoxic drugs is expected to decrease the morbidity associated with cancer chemotherapy. Thus, there is a great need for innovative approaches to improve the long-term survival of patients suffering with this disease.